Restorative Therapies after Stroke: Drugs, Devices and Robotics

Authors

  • MV Padma Srivastava Professor, Head Unit II Neurology, All India Institute of Medical Sciences, Ansari Nagar, Ring Road, New Delhi – 11 0 0 2 9 . E - m a i l : vasanthapadma123@gmail.com. Mob : 9868398261.

Keywords:

Cerebral stroke, stroke therapy, functional neuroimaging.

Abstract

Restorative therapies aim to improve outcome and function by promoting plasticity within a therapeutic time window between days to weeks to years. In this article, the mechanisms by which cell-based, pharmacological and robotic treatments stimulate endogenous brain remodelling after stroke, particularly neurogenesis, axonal plasticity and white-matter integrity are described with a brief outline of the potential of neuroimaging (fMRI) techniques. Stem cells aid stroke recovery via mechanisms depending on the type of cells used. Transplanted embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and neural stem cells (NSCs) can replace the missing brain cells in the Infarcted area, while adult stem cells, such as mesenchymal stem cells or multipotent stromal cells (MSCs) and MNCs, provide trophic support to enhance self-repair systems such as endogenous neurogenesis. Most preclinical studies of stem cell therapy for stroke have emphasized the need to enhance self-repair systems rather than to replace lost cells, regardless of the type of cells used. Noninvasive brain stimulation (NIBS) provides a valuable tool for interventional neurophysiology by modulating brain activity in a speciï¬c distributed, cortico-subcortical network. The two most commonly used techniques for noninvasive brain stimulation are transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). The article also discusses the potential role and current evidence for the use of pharmacological therapy, robotics and speciï¬c forms of physiotherapy regimes in optimizing stroke recovery. Neurorestoration is a concept that has been proven emphatically in several experimental models and clinical studies of stroke. Elucidating the underlying mechanisms of cell-based, pharmacological and rehabilitative therapies is of primary interest and crucial for translation of treatments to clinical use. The knowledge must provide an impetus for the development of superior, advanced and cost effective neuro restorative interventions that will enhance stroke recovery.

 

Keywords : Cerebral stroke, stroke therapy, functional neuroimaging.

References

Z h a n g Z G , C h o p p M ( 2 0 0 9 ) . Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurol 8(5):491-500.

Hacke W, Kaste M, Bluhmki E, et al (2008). Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. NEJM 359(13):1317-1329.

Grotta JC, Jacobs TP, Koroshetz WJ, Moskowitz MA (2008). Stroke program review group: an interim report. Stroke 39:1364-1370.

Burke E, Cramer SC (2013). Biomarkers and predictors of restorative therapy effects after stroke. Curr Neurol Neurosci Rep13: 329.

Kawamata T, Speliotes EK, Finklestein SP (1997). The role of polypeptide growth factors in recovery from stroke. In: Brain Plasticity. Freund HJ, Sabel BA, Witte OW, eds. Philadelphia : Lippincott-Raven, 377-382.

Kononen M, Tarkka IM, Niskanen E, et al (2012). Functional MRI and motor behavioral changes obtained with constraint-induced movement therapy in c h r o n i c s t r o k e . E u r J N e u r o l 19(4):578–586.

Cramer SC (2008). Repairing the human brain after stroke. II Restorative therapies. Annal Neurol 63(5):549-560.

Nudo RJ ( 2013 ) . Recovery after braininjury : mechanisms and principles. Front Hum Neurosci 7:1-9.

Young HE, Black AC Jr (2004). Adult stem cells. Anat Rec A Discov Mol Cell Evol Biol 276: 75-102.

Seaberg RM, van der Kooy D (2003). Stem and progenitor cells: the premature desertion of rigorous deï¬nitions. Trends Neurosci 26: 125-131.

Jaenisch R, Young R (2008). Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell 132: 567-582.

Tandon PN (2007). Brain cells--recently unveiled secrets: their clinical signiï¬cance. Neurol India 55: 322-327.

McKay R (1997). Stem cells in the central nervous system. Science 276: 66-71.

Takahashi K, Okita K, Nakagawa M, Yamanaka S (2007). Induction of pluripotent stem cells from ï¬broblast cultures. Nat Protoc 2: 3081-3089.

Yamanaka S (2007). Strategies, new developments in the generation of patient- speciï¬c pluripotent stem cells. Cell Stem Cell 1: 39-49.

Hess DC, Borlongan CV (2008). Stem cells and neurological diseases. Cell Prolif 41 Suppl 1: 94-114.

Yu G, Borlongan CV, Stahl CE, et al (2009). Systemic delivery of umbilical cord blood cells for stroke therapy: a review. Restor Neurol Neurosci 27:41-54.

Park CH, Minn YK, Lee JY, et al (2005). In vitro and in vivo analyses of human embryonic stem cell-derived dopamine neurons. J Neurochem 92: 1265-1276.

Perrier AL, Tabar V, Barberi T, et al (2004). Derivation of midbrain dopamine neurons from human embryonic stem cells. Proc Natl Acad Sci USA 101:2543- 2548.

Patkar S, Tate R, Modo M, Plevin R, Carswell HV (2012). Conditionally immortalised neural stem cells promote functional recovery and brain plasticity after transient focal cerebral ischemia in mice. Stem Cell Res 8:14-25.

Tabar V, Panagiotakos G, Greenberg ED, et al (2005). Migration and differentiation of neural precursors derived from human embryonic stem cells in the rat brain. Nat Biotechnol 23:601-606.

Vroemen M, Aigner L, Winkler J, Weidner N (2003). Adult neural progenitor cell grafts survive after acute spinal cord injury and integrate along axonal pathways. Eur J Neurosci 18: 743-751.

Evans MJ, Kaufman MH ( 1981 ) . Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154-156.

Lie DC, Dziewczapolski G, Willhoite AR, et al (2002). The adult substantia nigra contains progenitor cells with neurogenic potential. J Neurosci 22:6639-6649.

Morrison SJ, Uchida N, Weissman IL (1995). The biology of hematopoietic stem cells. Annu Rev Cell DevBiol 11: 35- 71.

Domen J, Weissman IL (1999). Self- renewal, differentiation or death: r e g u l a t i o n a n d m a n i p u l a t i o n o f hematopoietic stem cell fate. Mol Med Today 5: 201-208.

Ploemacher RE (1997). Stem cells: characterization and measurement. Bailliere's Clin Haematol 10: 429-444.

Bianco P, Riminucci M, Gronthos S, Robey PG (2001). Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells 19: 180-192.

Kolf CM, Cho E, Tuan RS (2007). Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation. Arthritis Res Ther 9:204.

Jiang Y, Jahagirdar BN, Reinhardt RL, e t a l ( 2 0 0 2 ) . P l u r i p o t e n c y o f mesenchymal stem cells derived from adult marrow. Nature 418:41-49.

Prockop DJ (1997). Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 276: 71-74.

Yu F, Li Y, Morshead CM (2013). Induced pluripotent stem cells for the treatment of stroke: the potential and the pitfalls. Current Stem Cell Res & Therapy 8(5):407-414.

Bhasin A, Srivastava MV, Mohanty S, Bhatia R, Kumaran SS (2013). Stem cell therapy: a clinical trial of stroke. Clin Neurol Neurosurg 115:1003- 1008.

Bhasin A, Srivastava MV, Bhatia R, et al ( 2 0 1 2 ) . A u t o l o g o u s i n t r a v e n o u s mononuclear stem cell therapy in chronic ischemic stroke. JSRM 8:181-189.

Bhasin A, Srivastava MV, Kumaran SS, et al (2011). Autologous mesenchymal stem cells in chronic stroke. Cerebrovasc Dis Extra 1: 93-104.

Meamar R, Dehghani L, Ghasemi L, Khorvash F, Shaygannejad V (2013). Stem cell therapy in stroke: a review of literature. Int J Prev Med 4(2):S139.

Bang YO (2016). Clinical trials of adult stem cell therapy in patients with ischemic stroke. J Clin Neurol 12(1):14-20.

Bhasin A, Srivastava MV, Mohanty S, et al ( 2016 ) . Paracrine mechanisms of intravenous bone marrow- derived mononuclear stem cells in chronic ischemic stroke. Cerebrovasc Dis Extra 6:107-119

Auriat AM, Neva JL, Peters S, Ferris JK, Boyd LA (2015). A review of transcranial magnetic stimulation and multimodal neuroimaging to characterize post-stroke neuroplasticity. Front Neurol 6:226-231.

Bindman LJ, Lippold OC, Redfearn JW (1964). Relation between the size and form of potentials evoked by sensory. J Physiol 171:1-25.

H o y e r E H , C e l h i k PA ( 2 0 1 1 ) . Understanding and enhancing motor recovery after stroke using transcranial magnetic stimulation. Restor Neurol Neurosc 29(6):395-409.

Reato D, Rahman A, Bikson M, Parra LC ( 2010 ) . Low- intensity e l ectrical stimulation affects network dynamics by modulating population rate and spike timing. J Neurosci 30(45) :15067–15079.

Corti M, Pattern C, Triggs W (2012). Repetitive t ranscranial magnetic stimulation of motor cortex after stroke. Arch Phy Med Rehabil 91(3):254-270.

Hsu WY, Cheng CH, Liao KK, Lee IH, Lin YY (2012). Effects of repetitive transcranial magnetic stimulation on motor functions in patients with stroke: a meta-analysis. Stroke 43 :1849–1857

Kubis N (2016). Non-Invasive Brain Stimulation to Enhance Post-Stroke Recovery. Front Neural Circuits10:56-62.

Cicinelli P, Pasqualetti P, Zaccagnini M ( 2006 ) . Imagery- induced cortical excitability changes in stroke: a transcranial magnetic stimulation study. Cereb Cortex 16(2):247-253.

Cicinelli P, Pasqualetti P, Zaccagnini M (2003). Interhemispheric asymmetries of motor cortex excitability in the post acute stroke stage: a paired pulse transcranial stimulation study. Stroke 34(11):2653- 2658.

Plautz EJ, Barbay S, Frost SB, et al (2003). Post-infarct cortical plasticity and behavioral recovery using concurrent cortical stimulation and rehabilitative training: a feasibility study in primates. Neurological Research 25: 801–810.

Kleim JA, Kleim ED, Cramer SC (2007). Systematic assessment of training- induced changes in corticospinal output to hand using frameless stereotaxic transcranial magnetic stimulation. Nature Protocols 2:1675–1684.

Gomez A, Schjetnan P, Faraji J, Gerlinde A, Tatsuno MM, Luczak A (2013). Transcranial Direct Current Stimulation in Stroke Rehabilitation: AReview of Recent Advancements. Review. Stroke Research and Treatment ; article ID170456.

Nitsche MA, Liebetanz D, Lang N, et al (2003). Safety criteria for transcranial direct current stimulation (tDCS) in h u m a n s . C l i n N e u r o p h y s i o l 11:2220–2223.

Leindenberg R, Rengha V, Zhu LL, Nair D, Schlaug G (2010). Bihemispheric brain stimulation facilitates motor recovery in chronic stroke patients. Neurology 75:2176-2184.

Kim DY, Ohn SH, Yang EJ, Park CI, Jung KJ (2009). Enhancing motor performance by anodal transcranial direct current stimulation in subacute stroke patients. A J Phy Med Rehabil 88:829-836.

Fregni S, Boggio PS, Mansur CG, et al (2005). Transcranial direct current stimulation of the unaffected hemisphere in stroke patients. Neuro Report 16:1551- 1555.

Webster BR, Celnik PA, Cohen LG (2006). Noninvasive brain stimulation in stroke rehabilitation. NeuroRx 3:474-481.

Ramachandran VS, Altschuler EL, Stone L, Al-Aboudi M, Schwartz E, Siva N (1999). Can mirrors alleviate visual hemineglect? Medical Hypotheses 52(4):303-305.

Dohle C, Pullen J, Nakaten A, Kust J, Rietz C, Karbe H (2009). Mirror therapy p r o m o t e s r e c o v e r y f r o m s e v e r e hemiparesis: a randomized controlled trial. Neurorehabil Neural Repair 23(3):209-217.

Bhasin A, Srivastava MV, Kumaran SS, Bhatia R, Mohanty S (2012). Neural interface of mirror therapy in chronic stroke. A functional magnetic resonance imaging study. Neurology India 60(6): 570-576.

Kwakkel G, Veerbeek JM, Wegen EEM, Wolf SL (2015). Constraint-Induced Movement Therapy after Stroke. Lancet Neurol 14(2):224-234.

Reiss A, Wolf S, Hammel E, McLeod E, Williams E (2012). Constraint-Induced Movement Therapy (CIMT): Current Perspectives and Future Directions. Stroke Research and Treatment 8:159391- 159396.

Nijland R, Kwakkel G, Bakers J, van Wegen E (2011). Constraint-induced movement therapy for the upper paretic limb in acute or sub-acute stroke: a s y s t e m a t i c r e v i e w. Int J S t roke 6(5):425–433.

S h e f fl e r L R , C h a e J ( 2 0 0 7 ) . Neuromuscular electrical stimulation in neurorehabilitation. Muscle & Nerve 35:562–590.

Quandt F, Hummel FC (2014). The influence of functional electrical stimulation on hand motor recovery in stroke patients: a review. Exp Transl Stroke Med 6:9-15.

Ada L, Foongchomcheay A (2002). Efï¬cacy of electrical stimulation in preventing or reducing subluxation of the shoulder after stroke: a meta-analysis. Aust J Physiother 48(4) : 257–267.

Masiero S, Celia A, Rosati G, Armani M (2007). Robotic-assisted rehabilitation of the upper limb after acute stroke. Arch Phys Med Rehabil 88(2):142-147.

Masiero S, Celia A, Armani M, Rosati G ( 2006 ) . A novel robot device in rehabilitation of post-stroke hemiplegic upper limbs. Aging Clin Exp Res 18(6):531-535.

Hornby TG, Campbell DD, Kahn JH, Demott T, Moore JL, Roth HR (2008). Enhanced gait-related improvements after therapist- versus robotic- assisted locomotor training in subjects with chronic stroke: a randomized controlled study. Stroke 39(6):1786-1792.

Mayr A, Kofler M, Quirbach E, Matzak H, F r ö h l i c h K , S a l t u a r i L ( 2 0 0 7 ) . Prospective, blinded, randomized crossover study of gait rehabilitation in stroke patients using the Lokomat gait orthosis. Neurorehabil Neural Repair 21(4):307-314.

Lo AC, Guarino PD, Richards LG, et al (2010). Robot-assisted therapy for long- term upper-limb impairment after stroke. N Engl J Med 362:1772-1783.

Palmer RM, Ferrige AG, Moncada S (1987). Nitric oxide release accounts for the biological activity of endothelium- derived relaxing factor. Nature 327: 524- 526.

Bredt DS, Snyder SH (1994). Nitric oxide: a physiologic messenger molecule. Annu Rev Biochem 63: 175-195.

Zhang RL, Zhang Z, Zhang L, et al (2006). Delayed treatment with sildenaï¬l enhances neurogenesis and improves functional recovery in aged rats after focal cerebral ischemia. J Neurosci Res 83: 1213-1219.

Berends HI, Nijlant JM, Movig KL, et al (2009). The clinical use of drugs influencing neurotransmitters in the brain to promote motor recovery after stroke; a Cochrane systematic review. Eur J Phys Rehabil Med 45: 621-630.

Clarkson AN, Huang BS, Macisaac SE, Mody I, Carmichael ST (2010). Reducing excessive GABA- mediated tonic inhibition promotes functional recovery after stroke. Nature 468: 305-309.

Acler M, Robol E, Fiaschi A, Manganotti P (2009). A double blind placebo RCT to investigate the effects of serotonergic modulation on brain excitability and motor recovery in stroke patients. J Neurol 256(7): 1152-1158.

Pariente J, Loubinoux I, Carel C, et al (2001). Fluoxetine modulates motor performance and cerebral activation of patients recovering from stroke. Ann Neurol 50(6): 718-729.

Chollet F, Tardy J, Albucher JF, et al (2011). Fluoxetine for motor recovery after acute ischemic stroke (FLAME): a randomized placebo-controlled trial. Lancet Neurol 10(2): 123-130.

Mead GE, Hsieh CF, Lee R, et al (2010). Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery. Cochrane Database Syst Rev 310(10):1066-1067.

Fagan SC, Waller JL, Nichols FT, et al ( 2010 ) . Minocycline to improve neurologic outcome in stroke (minos): A dose-ï¬nding study. Stroke 41(10): 2283- 2287.

Murata Y, Rosell A, Scannevin RH, et al (2008). Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke 39(12): 3372- 3377.

Padma MV, Bhasin A, Bhatia R, et al (2012). Efï¬cacy of minocycline in acute ischemic stroke: A single-blinded, placebocontrolled trial. Neurol India 60(1): 23-28

Yan T, Chopp M, Ye X, et al (2012). Niaspan increases axonal remodeling after stroke in type 1 diabetes rats. Neurobiol Dis 46:157-164.

Shehadah A, Chen J, Cui X, Roberts C, Lu M, Chopp M (2010). Combination treatment of experimental stroke with Niaspan and Simvastatin, reduces axonal damage and improves functional outcome. J Neurol Sci 94: 107–111.

Hosp JA, Luft AR (2011). Cortical plasticity during motor learning and recovery after ischemic stroke. Neural Plast 2011(2):871296.

Westlake KP, Nagarajan SS (2011). Functional connectivity in relation to motor performance and recovery after stroke. Front Syst Neurosci 5(2):8-13

Published

2017-01-01

Issue

Section

ARTICLES